The present invention relates to production of novel ortho-aminophenol analogs from chloramphenicol, and related substrate analogs.
Ortho-aminophenols are intermediates in the synthesis of polybenzoxazole polymers and biologically active compounds such as common phenoxazinones that exhibit anti-microbial properties. Microbes constantly acquire resistance to antibiotics; therefore, new antibiotics are required to combat the pathogenic strains of bacteria.
The common route for commercial chemical synthesis of aminophenols occurs in two steps, nitration of phenol followed by reduction of the nitro-group with a metal to make the amine. The influence of the hydroxyl moiety varies with each substrate. For example, for phenol the substitution is directed preferentially to the ortho-position, but for naphthalene the para-position is more readily attacked. In either case, yields are very low for mononitration of phenols and conditions needed are extreme.
Although, the use of whole cells is limited by the toxicity of the antibiotic substrate, the use of free enzymes obtained from microbes, such as the nitrobenzene reductase is employable if a continuous supply of the cofactor, NADPH, for catalytic activity is provided. The activity of nitrobenzene reductase and hydroxylaminobenzene (HAB) mutase in concert can be exploited to catalyze the conversion of a range of nitroaromatic compounds to yield novel ortho-aminophenols. Additionally, nitrobenzene can be reduced to HAB by a zinc-catalyzed chemical reduction reaction and a subsequent reaction containing the HAB mutase also yields novel ortho-aminophenols. However, the activity of enzymes and metal reactants are often optimal under dissimilar conditions, and so their combination in a single reaction system is often a limitation. Therefore, the use of sequential metal reaction and biocatalysts has recently started to receive attention and a few reports demonstrate the applicability of the approach. For example, the combined action of an immobilized glucose isomerase and a copper catalyst was reported for the conversion of D-glucose to D-mannitol. Encapsulated lipase enzymes are also reported in ‘one-pot’ reactions with rhodium catalysts for esterification and C-C bond hydrogenation reactions.
Accordingly, it is an object of the present invention to couple a zinc chemical reaction and the HAB mutase enzymatic reaction for the continuous conversion of chloramphenicol, and its analogs to produce aminophenol analogs.
Other objects and advantages of the invention will be set forth in part in the description which follows, and in part will be obvious from the description, or may be learned by practice of the invention. The objects and advantages of the invention may be realized and attained by means of the methods and combinations particularly pointed out in the appended claims.